Learned associations between stimuli and natural rewards are enhanced when discrepancies between anticipated and received reinforcement are encountered (e.g., "prediction errors"). For instance, during associative conditioning, operant behaviors and mesolimbic DA neuronal activity are decreased when anticipated reinforcement is not received and enhanced when unexpected reinforcement is presented. Ventral tegmental area DA neurons project to prefrontal cortex (PFC) and nucleus accumbens (NAcc) terminals. These regions are functionally interactive components of associative and higher order leaming, and undergo modifications in DA activity after chronic cocaine administration. However, it has yet to be determined whether PFC and NAcc DA responses during associative leaming with natural rewards reflect similar modifications during drug-associative learning, or if alterations in the PFC and DA activity occur through the course of cocaine-associative conditioning. To develop effective treatments for cocaine abusers with different drug experiences, it is crucial to understand cocaine experience-dependent changes in neural and behavioral functions. Our preliminary findings indicate that cocaine-induced associative learning is rapidly reflected in PFC and NAcc DA responsiveness to conditioned cues, but behavioral measures are less sensitive to change. The proposed experiments will utilize a self-administration/conditioning procedure in conjunction with in vivo microdialysis, behavioral activity assessment and immunohistochemical techniques to address the following aims: 1) To determine NAcc and PFC DA and behavioral activity levels in response to cocaine and cue-induced prediction errors after limited and extensive cocaine conditioning experience, 2) To determine whether changes in PFC DA neurotransmission modulate cocaine-associative changes in NAcc DA responses, and 3) To assess deltaFosB and Cdk5 overexpression after chronic cocaine self-administration, extinction and drug abstinence.